We have previously shown that methylazoxymethanol (MAM) acetate induces significant numbers of colon tumors in rats following a single treatment. The duodenum is the next most sensitive site for tumor formation. We have now found that of all the intestinal segments, only colon, duodenum, and cecum show marked inhibition of DNA synthesis acutely, while jejunum and ileum are less so affected. There appears to be a relationship between those segments affected markedly soon after treatment and the site of tumor development. We have eliminated as possible mechanisms for this selectivity differences in the extent of deacetylation of MAM acetate, differences in uptake and distribution of MAM acetate, and the role of biliary and fecal transport of active carcinogen. We propose that the selective toxicity may be the result of organ-specific enzymatic enhancement of MAM degradation to its reactive moiety, and that the selectivity in site of tumor formation may be due to differences in the nature and extent of DNA alterations induced within the various segments, and the rate of repair of such alterations. In the area of specific enhancement of MAM degradation, preliminary experiments show that addition of MAM to liver homogenates or high speed supernatant fractions results in 70% greater yield of formaldehyde (HCOH) after 1 hr than that found after adding MAM to buffer. We will attempt to identify a specific enzyme responsible for this enhancement and to determine whether such enzymatic effects occur in segments of intestine sensitive to this carcinogen. In the area of selective tumorigenicity, we will determine the extent of alkylation of DNA, specifically the formation of 7-methylguanine and 6-0-methylated bases. These studies will utilize both high pressure liquid chromatography and column chromatography techniques.